Neuropathology and Applied Neurobiology (2002), 28, 461–470 © 2002 Blackwell Publishing Ltd 461 Blackwell Science, LtdOxford, UK NANNeuropathology and Applied Neurobiology0305-1846Blackwell Science Ltd, 2002 28 417 Muscle pathology in dysferlinopathy M. Fanin and C. Angelini 10.1046/j.0305-1846.2002.00417.x Original Article461470BEES SGML Muscle pathology in dysferlin deficiency M. Fanin and C. Angelini Department of Neurological and Psychiatric Sciences, University of Padova, Italy M. Fanin and C. Angelini (2002) Neuropathology and Applied Neurobiology 28, 461–470 Muscle pathology in dysferlin deficiency Dysferlin deficiency is being increasingly recognized in limb-girdle dystrophy and distal myopathy but its role in the development of muscle pathology is still poorly understood. For this purpose, 26 muscle biopsies from 25 dysferlinopathy patients were analysed by routine his- tochemistry and by immunohistochemistry with eight dif- ferent antibodies, and scored for inflammatory response and type of cell infiltrate, fibre degeneration and regenera- tion, fibre type composition and severity of histopathologi- cal changes. In cases with an advanced-stage dystrophic pattern we observed type 1 fibre predominance exceeding 80%, suggesting a selective loss of type 2 fibres or a conver- sion process. The extent of muscle fibre regeneration and degen- eration in dysferlinopathy was intermediate between sarcoglycanopathy and Duchenne dystrophy or myositis, suggesting a rather aggressive course of the disease. An increased inflammatory response was observed in the majority of our patients (16/26), who also showed an active dystrophic pattern. Type and localization of cellu- lar infiltrates suggest that inflammatory reaction is sec- ondary to necrosis. Major histocompatibility complex (MHC) class I molecules were overexpressed in dysferlin- opathy, mainly in association with fibre phagocytosis and regeneration; their occasional expression in non-necrotic fibres might represent a marker of ongoing necrosis. Muscle inflammation might be triggered by the structur- ally altered membrane consequent to dysferlin defect. Keywords: Dysferlin, limb-girdle muscular dystrophy LGMD2B, Miyoshi myopathy, muscle pathology Correspondence: Dr M. Fanin, Department of Neurological and Psychiatric Sciences, University of Padova, via Giustiniani 5, 35128 Padova, Italy. Tel.: + 39 49 8213610; Fax: + 39 49 8751770; E- mail: marina.fanin@unipd.it Introduction Limb-girdle muscular dystrophy type 2B (LGMD2B) and the distal muscular dystrophy of Miyoshi (MM) are caused by mutations in the dysferlin gene [15,18,28], mapped to chromosome region 2p13. Although the clinical features of LGMD2B and MM are different, both phenotypes can be detected among patients belonging to the same family, thus sharing the same mutation [15,18,28]. The clinical heterogeneity might be attributed to additional epigenetic factors [15,18,23,27,28]; myoferlin, a protein homologue to dysferlin, has recently been suggested as a possible modifier gene in dysferlinopathy [7]. Dysferlin imm- unolocalizes to the sarcolemma similarly to dystrophin [1,20,24], but it does not associate with the dystrophin– glycoprotein complex. Its function and the mechanism by which it causes muscle fibre necrosis are still under investigation. Dysferlin presents a high degree of sequence homology with the protein Fer-1 in Caenorhabditis elegans [6]. Because the mutant worm has an abnormal sper- matogenesis, it was argued that mutant Fer-1 might be involved in the failure of membrane fusion between the organelles and plasmalemma. By analogy, the pathoge- netic mechanism in dysferlinopathies might be correlated with the abnormal trafficking of vesicles to sarcolemma, and might lead to abnormal repair of damaged muscle fibres. Molecular diagnosis of dysferlinopathy is now available, and several patients have been diagnosed and analysed. Several studies have reported a prominent inflammatory response in dysferlinopathy patients [4,5,12,21,23,25], but the origin of this feature is still unknown. It is also